3,4-dihydro-2H-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds

ABSTRACT

The invention provides novel compounds having the general formula (I) 
                         
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , A, m, n and p are as described herein, compositions including the compounds and methods of using the compounds.

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to aldosterone synthaseinhibitors for the treatment or prophylaxis of chronic kidney disease,congestive heart failure, hypertension, primary aldosteronism andCushing syndrome.

The present invention provides novel compounds of formula (I)

-   -   wherein    -   R¹, R², R³ and R⁴ are independently selected from H, alkyl and        cycloalkyl;    -   R⁵, R⁷ and R⁹ are independently selected from H or alkyl;    -   R⁸ and R¹¹ together form —CH₂—CH₂—;    -   R¹⁰ is H or R¹⁰ and R¹¹ together form —(CH₂)_(w)—;    -   or R⁶ and R⁹ together form —CH₂—, R⁸ is H and R¹⁰ and R¹¹        together form —CH₂—;    -   A is —C(O)— or —S(O)₂—;    -   B is —C— or —N—;    -   R¹² is cycloalkyl or substituted heteroaryl, wherein substituted        heteroaryl is substituted with one to three substituent        independently selected from H, alkyl, cycloalkyl, hydroxy,        alkoxy, cyano and halogen;    -   R¹³ is halogen, cyano, alkoxy or haloalkoxy;    -   R¹⁴ is H, alkyl or cycloalkyl;    -   R¹⁵ is H, alkyl, cycloalkyl or halogen;    -   m, n and p are independently selected from zero and 1;    -   w is 1, 2 or 3;    -   and pharmaceutically acceptable salts thereof.

Herein we describe inhibitors of aldosterone synthase that have thepotential to protect from organ/tissue damage caused by an absolute orrelative excess of aldosterone. Hypertension affects about 20% of theadult population in developed countries. In persons 60 years and older,this percentage increases to above 60%. Hypertensive subjects display anincreased risk of other physiological complications including stroke,myocardial infarction, atrial fibrillation, heart failure, peripheralvascular disease and renal impairment. The renin angiotensin aldosteronesystem is a pathway that has been linked to hypertension, volume andsalt balance and more recently to contribute directly to end organdamage in advanced stages of heart failure or kidney disease. ACEinhibitors and angiotensin receptor blockers (ARBs) are successfullyused to improve duration and quality of life of patients. These drugsare not yielding maximum protection. In a relatively large number ofpatients ACE and ARB's lead to so-called aldosterone breakthrough, aphenomenon where aldosterone levels, after a first initial decline,return to pathological levels. It has been demonstrated that thedeleterious consequences of inappropriately increased aldosterone levels(in relation to salt intake/levels) can be minimized by aldosteroneblockade with mineralocorticoid receptor antagonists. A directinhibition of aldosterone synthesis is expected to provide even betterprotection as it will also reduce non-genomic effects of aldosterone aswell.

The effects of aldosterone on Na/K transport lead to increasedre-absorption of sodium and water and the secretion of potassium in thekidneys. Overall this results in increased blood volume and, therefore,increased blood pressure. Beyond its role in the regulation of renalsodium re-absorption aldosterone can exert deleterious effects on thekidney, the heart and the vascular system especially in a “high sodium”context. It has been shown that under such conditions aldosterone leadsto increased oxidative stress which ultimately may contribute to organdamage. Infusion of aldosterone into renally compromised rats (either byhigh salt treatment or by unilaterally nephrectomy) induces a wide arrayof injuries to the kidney including glomerular expansion, podocyteinjury, interstitial inflammation, mesangial cell proliferation andfibrosis reflected by proteinuria.

More specifically aldosterone was shown to increase the expression ofthe adhesion molecule ICAM-1 in the kidney. ICAM-1 is criticallyinvolved in glomerular inflammation. Similarly, aldosterone was shown toincrease the expression of inflammatory cytokines, such as interleukinIL-1b and IL-6, MCP-1 and osteopontin. On a cellular level it wasdemonstrated that in vascular fibroblasts aldosterone increased theexpression of type I collagen mRNA, a mediator of fibrosis. Aldosteronealso stimulates type IV collagen accumulation in rat mesangial cells andinduces plasminogen activator inhibitor-1 (PAI-1) expression in smoothmuscle cells. In summary aldosterone has emerged as a key hormoneinvolved in renal damage. Aldosterone plays an equally important role inmediating cardiovascular risk.

There is ample preclinical evidence that MR-antagonists (spironolactoneand eplerenone) improve blood pressure, cardiac and renal function invarious preclinical models.

More recently preclinical studies highlight the important contributionof CYP11B2 to cardiovascular and renal morbidity and mortality. TheCYP11B2 inhibitor FAD286 and the MR antagonist spironolactone wereevaluated in a rat model of chronic kidney disease (high angiotensin IIexposure; high salt and uni-nephrectomy). Angiotensin II and high salttreatment caused albuminuria, azotemia, renovascular hypertrophy,glomerular injury, increased PAI-1, and osteopontin mRNA expression, aswell as tubulointerstitial fibrosis.

Both drugs prevented these renal effects and attenuated cardiac andaortic medial hypertrophy. Following 4 weeks of treatment with FAD286,plasma aldosterone was reduced, whereas spironolactone increasedaldosterone at 4 and 8 weeks of treatment. Similarly only spironolactonebut not FAD286 enhanced angiotensin II and salt-stimulated PAI-1 mRNAexpression in the aorta and the heart. In other studies the CYP11B2inhibitor FAD286 improved blood pressure and cardiovascular function andstructure in rats with experimental heart failure. In the same studiesFAD286 was shown to improve kidney function and morphology.

Administration of an orally active CYP11B2 inhibitor, LCI699, topatients with primary aldosteronism, lead to the conclusion that iteffectively inhibits CYP11B2 in patients with primary aldosteronismresulting in significantly lower circulating aldosterone levels and thatit corrected the hypokalemia and mildly decreased blood pressure. Theeffects on the glucocorticoid axis were consistent with a poorselectivity of the compound and a latent inhibition of cortisolsynthesis. Taken together these data support the concept that a CYP11B2inhibitor can lower inappropriately high aldosterone levels. Achievinggood selectivity against CYP11B1 is important to be free of undesiredside effects on the HPA axis and will differentiate different CYP11B2inhibitors.

The compounds of the present invention according formula (I) are potentinhibitors of CYPB 11B2 and present an improved selectivity towardsCYP11B2 versus CYP11B1 combined with an improved metabolic stability.

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of illnesses, especially in the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrome and the use of the said compounds,salts or esters for the production of medicaments for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrome.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms. In particular embodiments,alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4carbon atoms. Examples of alkyl include methyl, ethyl, propyl andisopropyl, n-butyl, iso-butyl, sec-butyl, and. Particular alkyl groupsinclude methyl, ethyl, propyl and isopropyl. More particular alkyl groupis methyl.

The term “cycloalkyl” denotes a monovalent saturated monocyclichydrocarbon group of 3 to 10 ring carbon atoms. In particularembodiments, cycloalkyl denotes a monovalent saturated monocyclichydrocarbon group of 3 to 8 ring carbon atoms. Examples for cycloalkylare cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.Particular cycloalkyl group is cyclopropyl.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo, or iodo. Particular halogens are chloro andfluoro. Particular halogen is chloro.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Examples of heteroaryl group include pyrrolyl, furanyl, thienyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl,benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl,benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particularheteroaryl group is pyridinyl. Also particular heteroaryl groups areimidazolyl, isoxazolyl, oxazolyl, pyrazolyl and pyrimidinyl. Furtherparticular heteroaryl groups are pyridinyl, imidazolyl, isoxazolyl andpyrazolyl.

The term “hydroxy” denotes a —OH group.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be prepared byaddition of an inorganic base or an organic base to the free acid. Saltsderived from an inorganic base include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium salts and thelike. Salts derived from organic bases include, but are not limited tosalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the hydrochloride salts, methanesulfonic acid salts and citric acidsalts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.μAdditionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes the group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups. Particularprotecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc). More particular protecting group is thetert-butoxycarbonyl (Boc).

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, but for the fact that one or moreatoms are replaced by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H (“T”), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P,³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically labeledcompounds of the present invention (e.g., those labeled with ³H or ¹⁴C)are useful in compound and/or substrate tissue distribution assays.Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present inventions can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting a non-isotopically labeledreagent with a isotopically labeled reagent. In particular, compounds offormula (I) wherein one or more H atom have been replaced by a ²H atomare also an embodiment of this invention.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention are compounds according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

The present invention also relates to compounds according to formuöa (I)as described herein, wherein

-   -   wherein    -   R¹, R², R³ and R⁴ are independently selected from H, alkyl and        cycloalkyl;    -   R⁵, R⁷ and R⁹ are independently selected from H or alkyl;    -   R⁸ and R¹¹ together form —CH₂—CH₂—;    -   R¹⁰ is H or R¹⁰ and R¹¹ together form —(CH₂)_(w)—;    -   or R⁶ and R⁹ together form —CH₂—, R⁸ is H and R¹⁰ and R¹¹        together form —CH₂—;    -   A is —C(O)— or —S(O)₂—;    -   R¹² is cycloalkyl or substituted heteroaryl, wherein substituted        heteroaryl is substituted with one to three substituent        independently selected from H, alkyl and halogen;    -   R¹³ is halogen;    -   R¹⁴ is H, alkyl or cycloalkyl;    -   R¹⁵ is H, alkyl, cycloalkyl or halogen;    -   m, n and p are independently selected from zero and 1;    -   w is 1, 2 or 3;    -   and pharmaceutically acceptable salts thereof.

Also an embodiment of the present invention are compounds according toformula (I) as described herein wherein A is —S(O)₂—.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein A is —C(O)—.

Also a particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein B is —C—.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹² is cycloalkyl orsubstituted pyridinyl, wherein substituted pyridinyl is substituted withone to three substituent independently selected from H, alkyl andhalogen.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹² is cycloalkyl orsubstituted pyridinyl, wherein substituted pyridinyl is substituted withone to three substituent independently selected from alkyl and halogen.

A more embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹² is cycloalkyl.

Another further embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹² is substitutedheteroaryl, wherein substituted heteroaryl is substituted with one tothree substituent independently selected from alkyl and halogen.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹² is substitutedpyridinyl, substituted imidazolyl or substituted pyrazolyl, whereinsubstituted pyridinyl, substituted imidazolyl and substituted pyrazolylsubstituted with one alkyl or halogen.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹² is substitutedpyridinyl, wherein substituted pyridinyl is substituted with one tothree substituent independently selected from alkyl and halogen.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹ and R² are independentlyselected from H and alkyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ and R² are alkyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹ and R² aremethyl.

Also a particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein m, n and p arezero.

A further particular of the present invention are compounds according toformula (I) as described herein, wherein w is 1 or 2.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R³ and R⁴ are H.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁵, R⁷ and R⁹ are H.

Also a particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁹ is H and R¹⁰and R¹¹ together form —(CH₂)_(w)—.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹⁴ is H or alkyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁴ is H.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹³ is cyano or halogen.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹³ is chloro.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁵ is H.

Particular examples of compounds of formula (I) as described herein areselected from

-   5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[[(3R or    3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[[(3S or    3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[[(3R or    3S)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[[(3S or    3R)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;-   5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;-   5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;-   5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3H-isoindol-1-one;-   5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;-   6-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;-   6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;-   6-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;-   6-Chloro-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;-   5-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl]amino]pyridin-3-yl]isoindol-1-one;

and pharmaceutically acceptable salts thereof.

Also particular examples of compounds of formula (I) as described hereinare selected from

-   5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;-   6-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;-   6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;-   6-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;-   5-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;-   5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;-   (3R or    3S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;-   (3S or    3R)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;-   (3R or 3    S)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one;-   (3S or    3R)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one;-   (3R or    3S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one;-   (3S or    3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one;-   2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;-   2-[5-[(1-Cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;-   2-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;-   2-[5-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as describedherein are selected from

-   5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-2-[5-[[(3S or    3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;-   5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;-   5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;

and pharmaceutically acceptable salts thereof.

Also further particular examples of compounds of formula (I) asdescribed herein are selected from

-   5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;-   6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;-   6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;-   5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;-   (3R or    3S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;-   2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;-   3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;

and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as describedherein are an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reaction and purification of the resultingproducts are known to those persons skilled in the art. In case amixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the man skilled in the art such ase.g. chiral chromatography or crystallization. The substituents andindices used in the following description of the processes have thesignificance given herein.

The following abbreviations are used in the present text:

AcOH=acetic acid, BOC=t-butyloxycarbonyl, BuLi=butyllithium,CDI=1,1-carbonyldiimidazole, DCM=dichloromethane,DBU=2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepine,DCE=1,2-dichloroethane, DIBALH=di-i-butylaluminium hydride,DCC=N,N′-dicyclohexylcarbodiimide, DMA=N,N-dimethylacetamide,DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide,EDCI=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,EtOAc=ethylacetate, EtOH=ethanol, Et₂O=diethylether, Et₃N=triethylamine,eq=equivalents,HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, HPLC=high performance liquid chromatography,HOBT=1-hydroxybenzo-triazole, Huenig's base=iPr₂NEt=N-ethyldiisopropylamine, IPC=in process control, LAH=lithium aluminium hydride,LDA=lithium diisopropylamide, LiBH₄=lithium borohydride, MeOH=methanol,NaBH₃CN, sodium cyanoborohydride, NaBH₄=sodium borohydride, NaI=sodiumiodide, Red-Al=sodium bis(2-methoxyethoxy) aluminium hydride, RT=roomtemperature, TBDMSCl=t-butyldimethylsilyl chloride, TFA=trifluoroaceticacid, THF=tetrahydrofuran, quant=quantitative.

Halogen or triflate, preferably iodo substituted pyridine compounds 2 or8 react with aryl lactams 1 in solvents like 1,4-dioxane, in thepresence of copper (I) iodide, potassium or cesium carbonate, achelating 1,2-diamino compound like N,N′-dimethylethylenediamine ortrans-1,2-diamino-cyclohexane or a chelating beta keto ester compoundlike 2-isobutyryl-cyclohexanone, at elevated temperatures, preferablewith the aid of microwave heating to form lactam substitutedheterocyclic compounds 3 and 5 as described in Scheme 1a and Scheme 1b(step a). Amino compounds 4 or 6 (compounds which are known or can bereadily prepared by methods known in the art) react with substitutedpyridine compounds 3 under similar conditions as used in step a (stepb), the conditions preferred for primary amino compounds 4 or 6 or byusing ‘Buchwald’ conditions, e.g. using catalysts like Pd(OAc)₂ andchelating ligands like Xanphos in the presence of a base like t-BuONa insolvents like dioxane at elevated temperature (conditions preferred forsecondary amino compounds 4 or 6) giving compounds 5 or 7. Compounds 5with R¹⁰¹ being a protecting group, e.g. the Boc group, can then beconverted into compounds 7 by removal of the protecting group R¹⁰¹ andreaction with a suitable activated carboxyl or sulfonyl compound (stepsc, d; Schemes 1a and 1b).

Carbamates 101 (Scheme 2a) react with polyphosphoric acid at elevatedtemperature (e.g. 100-180° C.) to form 3,4-dihydro-2H-isoquinolin-1-onederivatives 102 (step a). Trifluroacetamides 103 can be cyclized to1-(3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone compounds104 by treatment with paraformaldehyde in a mixture of concentratedsulfuric acid and acetic acid preferably around room temperature (stepb). Removal of the trifluoroacteyl group by treatment with e.g.potassium hydroxide in a solvent like ethanol at temperatures aroundroom temperature gives tetrahydro-isoquinoline compounds 105 (step c).Oxidation of tetrahydro-isoquinoline compounds 105 e.g. with iodosobenzene and potassium bromide preferably in water gives3,4-dihydro-2H-isoquinolin-1-one compounds 102 (step d). Reaction ofisoindole-1,3-dione compounds 106 (Scheme 2b) with a Grignard reagentR¹MgX in a solvent like THF preferably around 0° C. gives adducts 107(step e). Subsequent treatment with triethylsilane and boron trifluorideetherate in a solvent like dichloromethane and in a temperature rangepreferably between −25° C. and RT gives isoindolone compounds 108 (stepf). Introduction a methoxybenzyl protecting group into isoindolonecompounds 109 (e.g. by treatment with sodium bis(trimethylsilyl)amideand 1-bromomethyl-4-methoxy-benzene in THF between 0° C. and RT) givesprotected compounds 110 (step g); similarly, a methoxybenzyl protectinggroup can be introduced into compounds 108. Treatment of compounds 108carrying an additional methoxybenzyl protecting group or compounds 110with a base like sodium hydride in a solvent like THF and then with analkyl halide, mesylate or tosylate preferably between RT and the refluxtemperature of the solvent gives compounds 111 with structurallydifferent or structurally identical R¹ and R² groups (step h).Alternatively, treatment of compounds 108 carrying an additionalmethoxybenzyl protecting group or compounds 110 with a base like NaH,LDA or LiHMDS in solvents like DMF, tetrahydrofuran or1,2-dimethoxyethane and then with one or sequentially with two differentalkyl halides, mesylates or tosylates preferably between −78° C. and thereflux temperature of the solvent gives compounds 111 with structurallydifferent or structurally identical R¹ and R² groups (step h). Removalof the protecting group, e.g. by treatment with trifluoroacetic acid atelevated temperature gives isoindolone compounds 112 (step i).Alternatively (Scheme 2c), compounds 114 with R¹ and R² being alkylgroups can be obtained from cyano compounds 113 and suitable Grignardreagents, either by addition of two different reagents sequentially or asingle Grignard reagent in excess (to obtain compounds with identical R¹and R²) preferably in the presence of titanium tetra-isopropoxide insolvents like THF preferably in a temperature range between 0° C. and RT(step k). Compounds 114 with R¹═H and R² being an alkyl group can beobtained from cyano compounds 113 and suitable Grignard reagents insolvents like THF preferably in a temperature range between 0° C. and RT(step k) followed by reduction of the imine formed with sodiumborohydride in e.g. methanol around RT (step k). Compounds 114 undergoring closure by reaction with catalysts likedichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) in solventslike DMF in the presence of a base like iPr₂NEt preferably in atemperature range between about 100° C. and 150° C. in autoclave in thepresence of carbon monoxide (step 1).

Halogen or triflate substituted compounds 8 can be prepared by reactionof amino compounds 4 with di-halo or di-triflate substituted pyridines 2using conditions as described in Schemes 1 (Scheme 3) (step a).

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising

-   -   a) the reaction of a compound of formula (II) in the presence of        a compound of formula (III);

-   -   or    -   b) the reaction of a compound of formula (IV) in the presence of        a compound of formula (V);

-   -   wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,        R¹⁴, A, m, n and p are as described herein and X in step a) is        halogen or triflate and in step b) is halogen.

In particular, in step a), in the presence of copper (I) iodide,potassium or cesium carbonate, a chelating 1,2-diamino compound likeN,N′-dimethylethylenediamine or trans-1,2-diamino-cyclohexane or achelating beta keto ester compound like 2-isobutyryl-cyclohexanone, atelevated temperatures, preferable with the aid of microwave heating andin solvents like 1,4-dioxane.

In particular, in step b), in the presence of a base, such astriethylamine, in a solvent such as dichloromethane at a temperaturecomprise between −10° C. and RT.

Also an object of the present invention is a compound according toformula (I) as described herein for use as therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrome.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofdiabetic nephropathy.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofkidney or heart fibrosis.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofcongestive heart failure.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofhypertension.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofprimary aldosteronism.

A particular embodiment of the present invention is a compound accordingto formula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrome.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of diabetic nephropathy.

Another particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of kidney or heart fibrosis.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of chronic kidney disease.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of congestive heart failure.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of hypertension.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of primary aldosteronism.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of chronic kidney disease, congestive heartfailure, hypertension, primary aldosteronism and Cushing syndrome.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of diabetic nephropathy.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of kidney or heart fibrosis.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of chronic kidney disease.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of congestive heart failure.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of hypertension.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of primary aldosteronism.

Also an object of the invention is a method for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrome, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an object of the invention is a method for the treatment orprophylaxis of diabetic nephropathy, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an object of the invention is a method for the treatment orprophylaxis of kidney or heart fibrosis, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of chronic kidney disease, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of congestive heart failure, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of hypertension, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of primary aldosteronism, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a compound of formula (I)as described herein, when manufactured according to any one of thedescribed processes.

Assay Procedures

Herein we identified the use of the G-402 cell line as a host cell toectopically express (transiently or stably) enzymes of the CYP11 family.Specifically we developed stable G-402 cells expressing ectopicallyhuman CYP11B1, human CYP11B2, human CYP11A1, cynmolgus CYP11B1 orcynomolgus CYP11B2 enzyme activity. Importantly the identified cell lineG-402 expresses co-factors (adrenodoxin and adrenodoxin reductase)important for the activity of the CYP11 family and no relevant enzymeactivity of the CYP11 family (in comparison to H295R cells) was detectedin these cells. Therefore the G-402 cell line is uniquely suited as ahost cell for the ectopic expression of enzymes from the CYP11 family.

G-402 cells can be obtained from ATCC (CRL-1440) and were originallyderived from a renal leiomyoblastoma.

The expression plasmids contains the ORF for either human/cyno CYP11B1or CYP11B2 under the control of a suitable promoter (CMV-promoter) and asuitable resistance marker (neomycin). Using standard techniques theexpression plasmid is transfected into G-402 cells and these cells arethen selected for expressing the given resistance markers. Individualcell-clones are then selected and assessed for displaying the desiredenzymatic activity using 11-Deoxycorticosterone (Cyp11B2) or11-Deoxycortisol (Cyp11B1) as a substrate.

G-402 cells expressing CYP11 constructs were established as describedabove and maintained in McCoy's 5a Medium Modified, ATCC Catalog No.30-2007 containing 10% FCS and 400 μg/ml G418 (Geneticin) at 37° C.under an atmosphere of 5% CO2/95% air. Cellular enzyme assays wereperformed in DMEM/F12 medium containing 2.5% charcoal treated FCS andappropriate concentration of substrate (0.3-10 uM11-Deoxycorticosterone, 11-Deoxycortisol or Corticosterone). Forassaying enzymatic activity, cells were plated onto 96 well plates andincubated for 16 h. An aliquot of the supernatant is then transferredand analyzed for the concentration of the expected product (Aldosteronefor CYP11B2; Cortisol for CYP11B1). The concentrations of these steroidscan be determined using HTRF assays from CisBio analyzing eitherAldosterone or Cortisol.

Inhibition of the release of produced steroids can be used as a measureof the respective enzyme inhibition by test compounds added during thecellular enzyme assay. The dose dependent inhibition of enzymaticactivity by a compound is calculated by means of plotting addedinhibitor concentrations (x-axes) vs. measured steroid/product level(y-axes). The inhibition is then calculated by fitting the following4-parameter sigmoidal function (Morgan-Mercer-Flodin (MMF) model) to theraw data points using the least squares method:

$y = \frac{{AB} + {Cx}^{D}}{B + x^{D}}$wherein, A is the maximum y value, B is the EC50 factor determined usingXLFit, C is the minimum y value and D is the slope value.

The maximum value A corresponds to the amount of steroid produced in theabsence of an inhibitor, the value C corresponds to the amount ofsteroid detected when the enzyme is fully inhibited.

EC50 values for compounds claimed herein were tested with the G402-basedassay system described. Cyp11B2 enzyme activity was tested in presenceof 1 μM Deoxycorticosterone and variable amounts of inhibitors; Cyp11B1enzyme activity was tested in presence of 1 μM Deoxycortisol andvariable amounts of inhibitors.

EC50 EC50 human human CYP11B2 CYP11B1 Example nM nM 1 9 1254 2 4 450 30.4 18 4 2 56 5 1 133 6 1 4 7 230 >30000 8 365 19533 9 7 297 10 11 174511 3 1953 12 18 1826 13 7 4902 14 131 2892 15 148 9565 16 10 5345 17 1451912 18 9 1289 19 86 10910 20 55 3880 21 7 16909 22 23 2088 23 30 595424 1 6020 25 7 4359 26 16 1907 27 20 1134 28 27 533 29 29 5810 30 18 65231 12 6996 32 27 6140 33 31 29468 34 5 586 35 24 13331 36 22 1400 37 7010460 38 31 1203 39 25 13932 40 52 9574 41 17 190 42 56 10594

Compounds of formula (I) and their pharmaceutically acceptable salts oresters thereof as described herein have EC₅₀ (CYP11B2) values between0.000001 uM and 1000 uM, particular compounds have EC₅₀ (CYP11B2) valuesbetween 0.00005 uM and 500 uM, further particular compounds have EC₅₀(CYP11B2) values between 0.0005 uM and 50 uM, more particular compoundshave EC₅₀ (CYP11B2) values between 0.0005 uM and 5 uM. These resultshave been obtained by using the described enzymatic assay.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays) or rectally(e.g. in the form of suppositories). However, the administration canalso be effected parentally, such as intramuscularly or intravenously(e.g. in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragées andhard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should beappropriate. It will, however, be clear that the upper limit givenherein can be exceeded when this is shown to be indicated.

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of aldosterone mediated diseases.

The compounds of formula (I) or their pharmaceutically acceptable saltsand esters herein are inhibitiors of CYP11B2. The compounds of formula(I) or their pharmaceutically acceptable salts and esters herein displayalso variable inhibition of CYP11B1 but present an improved selectivitytowards CYP11B2 versus CYP11B1. Such compounds may be used for treatmentor prophylaxis of conditions displaying excessive cortisolproduction/levels or both excessive cortisol and aldosterone levels (forex.

Cushing syndrome, burn trauma patients, depression, post-traumaticstress disorders, chronic stress, corticotrophic adenomas, MorbusCushing).

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of cardiovascular conditions (includinghypertension and heart failure), vascular conditions, endothelialdysfunction, baroreceptor dysfunction, renal conditions, liverconditions, fibrotic diseases, inflammatory conditions, retinopathy,neuropathy (such as peripheral neuropathy), pain, insulinopathy, edema,edematous conditions, depression and the like.

Cardiovascular conditions include congestive heart failure, coronaryheart disease, arrhythmia, arterial fibrillation, cardiac lesions,decreased ejection fraction, diastolic and systolic heart dysfunction,fibrinoid necrosis of coronary arteries, cardiac fibrosis, hypertrophiccardiomyopathy, impaired arterial compliance, impaired diastolicfilling, ischemia, left ventricular hypertrophy, myocardial and vascularfibrosis, myocardial infarction, myocardial necrotic lesions, cardiacarrhythmias, prevention of sudden cardiac death, restenosis, stroke,vascular damage.

Renal conditions include acute and chronic renal failure, nephropathy,end-stage renal disease, diabetic nephropathy, decreased creatinineclearance, decreased glomerular filtration rate, expansion ofreticulated mesangial matrix with or without significanthypercellularity, focal thrombosis of glomerular capillaries, globalfibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignantnephrosclerosis (such as ischemic retraction, microalbuminuria,proteinuria, reduced renal blood flow, renal arteriopathy, swelling andproliferation of intracapillary (endothelial and mesangial) and/orextracapillary cells (crescents).

Renal conditions also include glomerulonephritis (such as diffuseproliferative, focal proliferative, mesangial proliferative,membranoproliferative, minimal change membranous glomerulonephritis),lupus nephritis, non-immune basement membrane abnormalities (such asAlport syndrome), renal fibrosis and glomerulosclerosis (such as nodularor global and focal segmental glomerulosclerosis).

Liver conditions include, but are not limited to, liver steatosis,nonalcoholic steatohepatitis, liver cirrhosis, liver ascites, hepaticcongestionand the like.

Vascular conditions include, but are not limited to, thrombotic vasculardisease (such as mural fibrinoid necrosis, extravasation andfragmentation of red blood cells, and luminal and/or mural thrombosis),proliferative arteriopathy (such as swollen myointimal cells surroundedby mucinous extracellular matrix and nodular thickening),atherosclerosis, decreased vascular compliance (such as stiffness,reduced ventricular compliance and reduced vascular compliance),endothelial dysfunction, and the like.

Inflammatory conditions include, but are not limited to, arthritis (forexample, osteoarthritis), inflammatory airways diseases (for example,chronic obstructive pulmonary disease (COPD)), and the like.

Pain includes, but is not limited to, acute pain, chronic pain (forexample, arthralgia), and the like.

Edema includes, but is not limited to, peripheral tissue edema, hepaticcongestion, liver ascites, splenic congestion, respiratory or lungcongestion, and the like.

Insulinopathies include, but are not limited to, insulin resistance,Type I diabetes mellitus, Type II diabetes mellitus, glucosesensitivity, pre-diabetic state, pre-diabetes, syndrome X, and the like.

Fibrotic diseases include, but are not limited to myocardial andintrarenal fibrosis, renal interstitial fibrosis and liver fibrosis.

Furthermore, the compounds of formula (I) or their pharmaceuticallyacceptable salts and esters as described herein can also be used for thetreatment or prophylaxis of cardiovascular condition selected from thegroup consisting of hypertension, heart failure (particularly heartfailure post myocardial infarction), left ventricular hypertrophy, andstroke.

In another embodiment, the cardiovascular condition is hypertension.

In particular embodiment, the cardiovascular condition istreatment-resistant hypertension.

In another embodiment, the cardiovascular condition is heart failure.

In another embodiment, the cardiovascular condition is left ventricularhypertrophy.

In another embodiment, the cardiovascular condition is congestive heartfailure, more particularly in patients with preserved left ventricularejection fraction.

In another embodiment, the cardiovascular condition is stroke.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis renal condition.

In another embodiment, the renal condition is nephropathy.

In another embodiment, the renal condition is auto-immuneglomerulonephritis.

In another embodiment, the chronic kidney disease is diabeticnephropathy.

In another embodiment, the fibrotic disease is kidney or heart fibrosis.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis Type II diabetes mellitus.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis Type I diabetes mellitus.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of diabetic retinopathy.

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be separated by methods describedherein or by methods known to the man skilled in the art, such as e.g.chiral chromatography or crystallization.

EXAMPLES

All examples and intermediates were prepared under argon atmosphere ifnot specified otherwise.

Intermediate A-1 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one

[A] [2-(3-Chloro-phenyl)-ethyl]-carbamic acid methyl ester

At 0° C., methyl chloroformate (4.6 g, 48 mmol) was added dropwise to asolution of 2-(3-chloro-phenyl)-ethylamine (5.0 g, 32 mmol) and Et₃N(6.4 g, 64 mmol) in DCM (100 mL). After the addition, the mixture wasstirred at room temperature for 0.5 hours. The organic layer was washedwith water (3×30 mL), 1N HCl (20 mL) and brine (30 mL), dried over anhy.Na₂SO₄, filtered and concentrated in vacuo. After vacuum drying, thetitle compound was obtained (6.49 g, 95%) as a white solid. MS: 214.1(M+H⁺).

[B] 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one

Under N₂ protection, a mixture of [2-(3-chloro-phenyl)-ethyl]-carbamicacid methyl ester (5.0 g, 23.4 mmol) and PPA (polyphosphoric acid) (20g) in a 250 mL round-bottom flask was vigorously stirred at 120° C. for2 hours. After cooling to room temperature, the reaction mixture wastreated with ice-water and aqueous ammonia solution to adjust the pH to8. Then, the mixture was extracted with EtOAc, and the organic layer waswashed with brine, dried over anhy. Na₂SO₄ and filtered. After removalof solvent under reduced pressure, the crude product obtained wasfurther washed with ethyl ether to give the title compound (1.66 g, 39%)as a white solid. MS: 182.0 (M+H⁺).

Intermediate A-2 5-Chloro-3-methyl-2,3-dihydro-isoindol-1-one

[A] 1-(2-Bromo-5-chloro-phenyl)-ethylamine

To a stirred solution of 2-bromo-5-chlorobenzonitrile (80 g, 370 mmol)in THF (1000 mL) at 0° C. was added EtMgBr (370 mL, 1110 mmol) dropwise.The reaction mixture was stirred at 0-5° C. for 5 hours before MeOH (500mL) was added dropwise. After the solution was stirred for another 15min, NaBH₄ (28 g, 740 mmol) was added carefully and the resultingmixture was stirred at room temperature for 16 hours. The reactionsolution was then poured into water and exacted with EtOAc (3×200 mL).The combined organic layers were dried over anhy. Na₂SO₄, filtered andconcentrated in vacuo to give a crude product, which was purified bycolumn chromatography (petroleum ether:EtOAc=3:1) to afford the titlecompound (30 g, 34.6%) as yellowish oil. MS: 235.5 [M+H⁺].

[B] 5-Chloro-3-methyl-2,3-dihydro-isoindol-1-one

A mixture of 1-(2-bromo-5-chlorophenyl)-ethylamine (30 g, 127.9 mmol),Pd(dppf)Cl₂ (3.2 g, 12.79 mmol), and DIPEA (49.5 g, 383.7 mmol) in DMF(1.2 L) was stirred in an autoclave under 2 MPa of CO at 130° C. for 24hours. After the reaction was cooled to room temperature, the reactionmixture was diluted with EtOAc (500 mL). The organic layer was washedwith brine, filtered, and concentrated in vacuo to give a crude product,which was purified by chromatography (PE:EtOAc=3:1) to give the titlecompound (5.2 g, 22.5%) as a brown solid. MS: 181.7 [M+H⁺].

Intermediate A-3 5-Chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

[A] 1-(2-Bromo-5-chloro-phenyl)-1-methyl-ethylamine

To a stirred solution of 2-bromo-5-chloro-benzonitrile (10 g, 46 mmol)in THF (200 mL) at 0° C., was added MeMgBr (77 mL, 230 mmol) dropwise.The reaction mixture was allowed to warm up to room temperature andstirred for 2 hours. Ti(Oi-Pr)₄ (13 g, 46 mmol) was added and thesolution was stirred for another 16 hours before it was quenched withaq. HCl solution and washed with EtOAc. The aqueous phase was adjustedto pH ˜10 with aq. NaOH solution, and exacted with EtOAc (3×100 mL). Thecombined organic layers were concentrated to give a crude title product(3.8 g, yield 33%) as oil, which was used directly in the next stepwithout further purification. MS: 249.30 (M+H⁺)

[B] 5-Chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

A mixture of 1-(2-bromo-5-chloro-phenyl)-1-methyl-ethylamine (3.8 g,15.3 mmol), Pd(dppf)Cl₂ (0.4 g, 0.55 mmol) and DIPEA (6 g, 45.9 mmol) inDMF (20 mL) was stirred in an autoclave under 2 MPa of CO at 130° C. for16 hours. Then, it was cooled to room temperature and the reactionmixture was diluted with EtOAc (300 mL). The organic layer was washedwith brine (2×80 mL), filtered, and concentrated in vacuo to give acrude product, which was purified by chromatography to give the titlecompound (1.13 g, 38%) as a brown solid. MS: 195.70 (M+H⁺)

Intermediate A-43,3-Dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

[A] 4-Bromo-2-methyl-benzoic acid methyl ester

To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in 115mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowlyand the reaction mixture was stirred at 70° C. for 2 hours before it wasconcentrated to afford a crude product which was then purified by columnchromatography to give the title compound (30.03 g, 93.6%) as a solid.

[B] 4-Cyano-2-methyl-benzoic acid methyl ester

A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180° C. for 5 hoursbefore it was poured into ice-water. The solid precipitate was collectedby vacuum filtration to give a crude product which was then purified bycolumn chromatography to afford the title compound (12.53 g, 63%) as asolid.

[C] 2-Bromomethyl-4-cyano-benzoic acid methyl ester

A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g,3.28 mmol) in CCl₄ (200 mL) was heated to reflux temperature for 3hours. After cooling to room temperature, the reaction mixture wasfiltered. The filtrate was concentrated in vacuo to give a crude product(18.2 g) which was used in the next step reaction without furtherpurification.

[D] 2-(4-Methoxy-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

To a solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester (18.1g, 71.24 mmol) in THF (300 mL) was added PMBNH₂ (23.4 g, 178.1 mmol) at0° C. and the reaction mixture was stirred at room temperature for 16hours. After vacuum filtration, the filtrate was concentrated in vacuo.The residue obtained was re-dissolved in EtOAc and washed with water andbrine. The organic layer was dried over anhy. Na₂SO₄, filtered, andconcentrated in vacuo to give a crude product which was purified bycolumn chromatography to give the title compound as a solid (11.69 g,56.0%).

[E]2-(4-Methoxy-benzyl)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

To a solution of2-(4-methoxy-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (11.6g, 41.7 mmol) in THF (300 mL) was added NaH (8.34 g, 208.4 mmol, 60% inmineral oil) and the reaction mixture was stirred at room temperaturefor 1 hour before iodomethane (35.5 g, 250.1 mmol) was added. After theaddition, the reaction mixture was stirred at 70° C. for 2 hours untilall the starting material was consumed. After cooling to roomtemperature, satd. aq. NH₄Cl solution was added and the mixture wasextracted with EtOAc (200 mL×3). The combined organic layers were driedover anhy. MgSO₄, filtered, and concentrated under reduced pressure togive a crude product which was purified by column chromatography toafford the title compound (7.22 g, 56.5%) as a solid.

[F] 3,3-Dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

To a solution of2-(4-methoxy-benzyl)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile(3.5 g, 11.42 mmol) in MeCN (70 mL) was added CAN (18.79 g, 34.27 mmol)in 30 mL of water at 0° C. The resulting reaction mixture was stirred at0° C. for 1 hour until all the starting material was consumed. Thereaction mixture was extracted between water and EtOAc and the combinedorganic layers were dried over anhy. MgSO₄, filtered, and concentratedunder reduced pressure to give a crude product which was purified bycolumn chromatography to afford the title compound (1.06 g, 49.8%) as asolid.

Intermediate A-5 3,5-Diiodo-pyridine

A mixture of 3,5-dibromopyridine (20 g, 84 mmol), CuI (4.76 g, 25 mmol),KI (83.7 g, 504 mmol) and N¹,N²-dimethylethane-1,2-diamine (4.4 g, 50.4mmol) in dioxane (400 mL) was stirred at 110° C. for 16 hours. Duringthis time, the reaction progress was monitored by LC/MS. The reactionmixture was filtered and the filtrate was concentrated under reducedpressure to afford a solid, which was then washed with EtOAc (100 mL)and DCM (100 mL) to give the crude title compound as a gray solid (13 g,47%). MS: 331.50 (M+H⁺). It was used in the next step without furtherpurification.

Intermediate A-63-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylicacid tert-butyl ester

[A]5-Chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one

In a 75-mL sealed tube, 3,5-diiodo-pyridine (intermediate A-5, 6.6 g, 20mmol), 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediateA-3, 1.95 g, 10 mmol), CuI (571 mg, 3 mmol), K₃PO₄ (4.24 g, 20 mmol) and(+)-(S,S)-1,2-diaminocyclohexane (0.7 mL, 6 mmol) were dissolved in 20mL of dioxane. The resulting reaction mixture was heated at 120° C. for3 hours before it was poured into water (50 mL) and extracted with EtOAc(2×125 mL). The combined organic layers were washed with brine, driedover anhy. Na₂SO₄, filtered and concentrated in vacuo to give a crudeproduct, which was purified by silica gel flash chromatography (0-30%EtOAc-hexane gradient) to yield the title compound (1.8 g, 45%) as alight yellow solid. MS: 399.2 (M+H⁺).

[B]3-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylicacid tert-butyl ester

A mixture of5-chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one(2.16 g, 5.4 mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester(1.8 g, 10.8 mmol), CuI (103 mg, 0.54 mmol), Cs₂CO₃ (3.5 g, 10.8 mmol)and 2-isobutyryl-cyclohexanone (0.36 mL, 2.16 mmol) in DMF (12 mL) werestirred at 100° C. for 12 hours. After cooling to room temperature, thereaction mixture was poured into water (20 mL) and extracted with EtOAc(2×100 mL). The combined organic layers were washed with brine, driedover anhy. Na₂SO₄, filtered and concentrated in vacuo to give a crudeproduct, which was purified by silica gel flash chromatography (30-100%EtOAc-hexane gradient) to yield the title compound (1.1 g, 48%) as alight yellow foam. MS: 443.2 (M+H⁺).

The following intermediates listed in Table 1 were prepared in analogyto the procedures described for the preparation of intermediate A-6,using appropriate reaction partners.

TABLE 1 MS Intermediate Name Reactants (M + H⁺) A-73-[5-(5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylic acid tert-butyl ester  

5-Chloro-3-methyl-2,3- dihydro-isoindol-1-one (Intermediate A-2), 3,5-diiodo-pyridine (Intermediate A-5), and 3-amino-azetidine- 1-carboxylicacid tert- butyl ester 429.1 A-83-[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylic acid tert-butyl ester  

6-Chloro-3,4-dihydro-2H- isoquinolin-1-one (Intermediate A-1), 3,5-diiodo-pyridine (Intermediate A-5), and 3-amino-azetidine-1- carboxylicacid tert-butyl ester 429.1 A-93-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-piperidine-1-carboxylic acid tert-butyl ester  

5-Chloro-3,3-dimethyl- 2,3-dihydro-isoindol-1-one (Intermediate A-3),3,5- diiodo-pyridine (Intermediate A-5), and 3- amino-piperidine-1-carboxylic acid tert-butyl ester 471.1 A-106-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butylester  

5-Chloro-3,3-dimethyl- 2,3-dihydro-isoindol-1-one (Intermediate A-3),3,5- diiodo-pyridine (Intermediate A-5), and 6- amino-2-aza-spiro[3.3]heptane-2- carboxylic acid tert-butyl ester 483.1 A-11tert-Butyl 3-[[5-(6-cyano-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]amino]azetidine-1-carboxylate  

3,3-Dimethyl-1-oxo-2,3- dihydro-1H-isoindole-5- carbonitrile(Intermediate A-4), 3,5-diiodo-pyridine (Intermediate A-5), and 3-amino-azetidine-1- carboxylic acid tert-butyl ester 434.1 A-12tert-Butyl 4-[[5-(6-cyano-[1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]amino]piperidine-1-carboxylate  

3,3-Dimethyl-1-oxo-2,3- dihydro-1H-isoindole-5- carbonitrile(Intermediate A-4), 3,5-diiodo-pyridine (Intermediate A-5), and 4-amino-piperidine-1- carboxylic acid tert-butyl ester 462.1

Example 15-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

[A]2-[5-(Azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

A mixture of3-[5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]-azetidine-1-carboxylicacid tert-butyl ester (Intermediate A-6, 360 mg, 0.812 mmol), acetylchloride (0.56 mL) in methanol (12 mL) was stirred at room temperaturefor 2 hours. After concentration under reduced pressure, it gives acrude product as light yellow foam, which was used in the next stepwithout further purification. MS: 343.2 (M+H⁺).

[B]5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

To a stirred solution of2-[5-(azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one(56 mg, 0.163 mmol) and Et₃N (0.5 mL) in DCM (5 mL) was addedcyclopropanesulfonyl chloride (30 mg, 0.21 mmol) at 0° C. and stirringat 0° C. was continued for 1 hour. The resulting reaction mixture wasextracted with EtOAc (2×100 mL) and the combined organic layers werewashed with brine, dried over anhy. Na₂SO₄, filtered and concentrated invacuo to give a crude product, which was purified by Prep-HPLC to affordtitle compound (22 mg, 30%) as a white foam. MS: 447.1 (M+H⁺).

Example 25-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one

To a stirred solution of2-[5-(azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one(Example 1 [A], 56 mg, 0.163 mmol) and Et₃N (0.5 mL) in DCM (5 mL) wasadded HATU (124 mg, 0.326 mmol) and 1-methylimidazole-2-carboxylic acid(27 mg, 0.212 mmol) at room temperature and stirring was continued atroom temperature for 1 hour. The resulting reaction mixture wasextracted with EtOAc (2×50 mL) and the combined organics were washedwith brine, dried over anhy. Na₂SO₄, filtered and concentrated in vacuoto give a crude product, which was purified by Prep-HPLC to afford titlecompound (15.4 mg, 21%) as a white foam. MS: 451.1 (M+H⁺).

Example 35-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

[A]3-{[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-yl]-methyl-amino}-azetidine-1-carboxylicacid tert-butyl ester

A mixture of5-chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one(398 mg, 1 mmol, intermediate A-6 [A]),3-methylamino-azetidine-1-carboxylic acid tert-butyl ester (250 mg, 1.3mmol), Pd(OAc)₂ (35 mg, 10% of weight), Xanphos (70 mg, 20% of weight)and t-BuONa (192 mg, 2 mmol) in dioxane (6 mL) was stirred at 115° C.for 2 hours. After cooling to room temperature, the reaction mixture waspoured into water (20 mL) and extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with brine, dried over anhy. Na₂SO₄,filtered and concentrated in vacuo to give a crude product, which waspurified by silica gel flash chromatography (40-100% EtOAc-hexanegradient) to yield the title compound (196 mg, 43%) as a light yellowfoam. MS: 457.1 (M+H⁺).

[B]2-[5-(Azetidin-3-yl-methyl-amino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one

A mixture of3-{[5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-yl]-methyl-amino}-azetidine-1-carboxylicacid tert-butyl ester (196 mg, 0.43 mmol), acetyl chloride (0.56 mL) inmethanol (12 mL) was stirred at room temperature for 2 hours. It wasthen concentrated in vacuo to give a crude product as a light yellowfoam. It was used in the next step of reaction without furtherpurification. MS: 357.2 (M+H⁺).

[C]5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

To a stirred solution of2-[5-(azetidin-3-yl-methyl-amino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one(60 mg, 0.17 mmol) and Et₃N (0.50 mL) in DCM (5 mL) was addedcyclopropanesulfonyl chloride (31 mg, 0.22 mmol) at 0° C. and stirringat 0° C. was continued for 1 hour. The resulting mixture was extractedwith EtOAc (2×100 mL) and combined organics were washed with brine,dried over anhy. Na₂SO₄, filtered and concentrated in vacuo to afford acrude product, which was purified by Prep-HPLC to afforded titlecompound (19 mg, 24%) as white foam. MS: 461.1 (M+H⁺).

Example 4 and Example 5 (+)-5-Chloro-2-[5-[[(3R or3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-oneand (−)-5-chloro-2-[5-[[(3S or3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one

Example 4, (+)-(—R or S)

Example 5, (−)-(S or R)

[A]3-{[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-yl]-methyl-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester

In analogy to the procedure described for the preparation of Example 3[A], 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester wasused to give the title compound as a light yellow foam (47%). MS: 471.1(M+H⁺).

[B]5-Chloro-3,3-dimethyl-2-[5-(methyl-pyrrolidin-3-yl-amino)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of Example 3[B], the title compound was obtained as a crude product of light yellowfoam. It was used in the next step without further purification. MS:371.2 (M+H⁺).

[C](rac)-5-Chloro-2-{5-[(1-cyclopropylsulfonyl-pyrrolidin-3-yl)-methyl-amino]-pyridin-3-yl}-3,3-dimethyl-2,3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of Example 3[C], cyclopropanesulfonyl chloride was used to yield the title compound(105 mg, 40%) as a racemic mixture of white foam. MS: 475.1 (M+H⁺).

[D] (+)-5-Chloro-2-[5-[[(3R or3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one(Example 4) and (−)-5-chloro-2-[5-[[(3S or3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one(Example 5)

Example 4, (+)-(R or S)

Example 5, (−)-(S or R)

The title compounds were prepared by chiral separation of(rac)-5-chloro-2-{5-[(1-cyclopropylsulfonyl-pyrrolidin-3-yl)-methyl-amino]-pyridin-3-yl}-3,3-dimethyl-2,3-dihydro-isoindol-1-oneon a Chiralpak IA column (10% ACN in ethanol) to give(+)-5-chloro-2-[5-[[(3R or3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one(10 mg, 20%, example 4), MS: 475.1 (M+H⁺) and (−)-5-chloro-2-[5-[[(3S or3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one(12.5 mg, 25%, example 5) as off-white foam. MS: 475.1 (M+H⁺).

The following examples listed in Table 2 were prepared in analogy to theprocedures described for the preparation of examples 1, 2, 3, 4 (or 5)by using appropriate starting materials:

TABLE 2 Ex Name/Structure/MS (M + H⁺) Reactant Reference 65-Chloro-2-[5-(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one  

  489.1 5-Chloro-3,3- dimethyl-2-[5- (methyl- piperidin-4-yl- amino)-pyridin-3-yl]- 2,3-dihydro- isoindol-1-one and cyclopropane sulfonylchloride Expl. 3 7 (+)-5-Chloro-2-[5-[[(3R or3S)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one.  

  475.1 3-[5-(6- Chloro-1,1- dimethyl-3- oxo-1,3- dihydro-isoindol-2-yl)- pyridin-3- ylamino]- piperidine-1- carboxylic acidtert-butyl ester (Intermediate A-9) and cyclopropyl sulfonyl chlorideExpl. 4 and chiral separation 8 (−)-5-Chloro-2-[5-[[3S or3R)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one  

  475.1 3-[5-(6- Chloro-1,1- dimethyl-3- oxo-1,3- dihydro-isoindol-2-yl)- pyridin-3- ylamino]- piperidine-1- carboxylic acidtert-butyl ester (Intermediate A-9) and cyclopropyl sulfonyl chlorideExpl. 4 and chiral separation 95-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one  

  482.1 2-[5-(azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3-dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 3-chloropyridine- 2-carboxylic acid Expl. 2 105-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one  

  462.1 2-[5-(azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3-dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 4-methylpyridine- 3-carboxylic acid Expl. 2 115-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one  

  462.1 2-[5-(azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3-dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 5-methylpyridine- 3-carboxylic acid Expl. 2 125-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one  

  468.1 3-[5-(5- Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate 7) and 3- chloropyridine- 2-carboxylic acid Expl. 2 135-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3H-isoindol-1-one  

  448.1 3-[5-(5- Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate 7) and 4- methylpyridine- 3-carboxylic acid Expl. 2 145-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one  

  433.1 3-[5-(5- Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-7) and cyclopropane- sulfonyl chloride Expl. 1 156-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one  

  433.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-8) and cyclopropane- sulfonyl chloride Expl. 1 166-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one  

  448.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-8) and 4- methylpyridine- 3-carboxylic acid Expl. 2 176-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one  

  468.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-8) and 3- chloropyridine- 2-carboxylic acid Expl. 2 186-Chloro-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one  

  448.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-8) and 4- methylpyridine- 3-carboxylic acid Expl. 2 195-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl]amino]pyridin-3-yl]isoindol-1-one  

  502.1 6-[5-(6- Chloro-1,1- dimethyl-3- oxo-1,3- dihydro-isoindol-2-yl)- pyridin-3- ylamino]-2-aza- spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Intermediate 10) and 4-methylpyridine- 3-carboxylic acid Expl. 2 206-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one  

  452.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-8) and 3,5- dimethylisoxazole- 4-carboxylic acid Expl. 221 6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one  

  437.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro- 1H- isoquinolin-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-8) and 1- methylpyrazole- 4-carboxylic acid Expl. 2 226-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one  

  437.1 3-[5-(6- Chloro-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-pyridin-3- ylamino]- azetidine-1- carboxylic acid tert-butyl ester(Intermediate A-8) and 1- methylimidazole- 2-carboxylic acid Expl. 2 235-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one  

  466.1 2-[5-(Azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3-dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 3,5-dimethylisoxazole- 4-carboxylic acid Expl. 2 245-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one  

  451.1 2-[5-(Azetidin- 3-ylamino)- pyridin-3-yl]- 5-chloro-3,3-dimethyl-2,3- dihydro- isoindol-1-one (Example 1[A]) and 1-methylpyrazole- 4-carboxylic acid Expl. 2 25 (3R or3S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one  

  448.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3-ylamino]- azetidine-1- carboxylic acid tert-butyl ester (IntermediateA-7) and 4- methylpyridine-3- carboxylic acid Expl. 2 and chiralseparation 26 (3S or 3R)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one  

  448.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3-ylamino]- azetidine-1- carboxylic acid tert-butyl ester (IntermediateA-7) and 4- methylpyridine- 3-carboxylic acid Expl. 2 and chiralseparation 27 (3R or3S)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one  

  468.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3-ylamino]- azetidine-1- carboxylic acid tert-butyl ester (IntermediateA-7) and 3- chloropyridine- 2-carboxylic acid Expl. 2 and chiralseparation 28 (3S or3R)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one  

  468.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3-ylamino]- azetidine-1- carboxylic acid tert-butyl ester (IntermediateA-7) and 3- chloropyridine- 2-carboxylic acid Expl. 2 and chiralseparation 29 (3R or3S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one  

  433.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3-ylamino]- azetidine-1- carboxylic acid tert-butyl ester (IntermediateA-7) and cyclopropane- sulfonyl chloride Expl. 1 and chiral separation30 (3S or 3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one  

  433.1 Chloro-3- methyl-1-oxo- 1,3-dihydro- isoindol-2-yl)- pyridin-3-ylamino]- azetidine-1- carboxylic acid tert-butyl ester (IntermediateA-7) and cyclopropane- sulfonyl chloride Expl. 1 and chiral separation31 2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile  

  438.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) andcyclopropane- sulfonyl chloride Expl. 1 323,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  453.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 4-methylpyridine- 3-carboxylic acid Expl. 2 333,3-Dimethyl-2-[5-[[1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  442.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 1-methylpyrazole- 4-carboxylic acid Expl. 2 343,3-Dimethyl-2[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  442.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 1-methylimidazole- 2-carboxylic acid Expl. 2 352-[5-[(1-Cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile  

  466.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) andcyclopropane- sulfonyl chloride Expl. 1 362-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile  

  501.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 3-chloropyridine- 2-carboxylic acid Expl. 2 373,3-Dimethyl-2[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  481.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 4-methylpyridine- 3-carboxylic acid Expl. 2 382-[5-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile  

  473.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 3-chloropyridine- 2-carboxylic acid Expl. 2 393,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  442.1 tert-Butyl 3- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] azetidine-1- carboxylate (Intermediate 11) and 3-methylimidazole- 4-carboxylic acid Expl. 2 403,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  470.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 1-methylpyrazole- 4-carboxylic acid Expl. 2 413,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  470.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 1-methylimidazole- 2-carboxylic acid Exp1. 2 423,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile  

  470.1 tert-Butyl 4- [[5-(6-cyano- 1,1-dimethyl- 3-oxo- isoindolin-2-yl)-3- pyridyl]amino] piperidine-1- carboxylate (Intermediate 12) and 3-methylimidazole- 4-carboxylic acid Expl. 2

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

The invention claimed is:
 1. A Compound of formula (I)

wherein R¹, R², R³ and R⁴ are independently selected from H, alkyl andcycloalkyl; R⁵, R⁷ and R⁹ are independently selected from H or alkyl; R⁸(i) is hydrogen and both R⁶ and R⁹ together are —CH₂—, and, R¹⁰ and R¹¹together are —CH₂—; or, (ii) and R⁶, R⁹ and R¹¹ are independently H oralkyl, and R¹⁰ is H; or, (iii) and both R⁶ and R⁹ are independently H oralkyl and R¹⁰ and R¹¹ together are —CH₂—; or, (iv) and R¹¹ together are—CH₂—CH₂—; and R⁶ and R¹⁰ are independently H or alkyl; A is —C(O)— or—S(O)₂—; B is —C— or —N—; R¹² is cycloalkyl or substituted heteroaryl,wherein substituted heteroaryl is substituted with one to threesubstituent independently selected from H, alkyl, cycloalkyl, hydroxy,alkoxy, cyano and halogen; R¹³ is halogen, cyano, alkoxy or haloalkoxy;R¹⁴ is H, alkyl or cycloalkyl; R¹⁵ is H, alkyl, cycloalkyl or halogen;m, n and p are independently selected from zero and 1; w is 1, 2 or 3;or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein A is —S(O)₂—.
 3. The compound according to claim 1,wherein A is —C(O)—.
 4. The compound according to claim 1, wherein R¹²is cycloalkyl or substituted pyridinyl, wherein substituted pyridinyl issubstituted with one to three substituent independently selected from H,alkyl and halogen.
 5. The compound according to claim 1, wherein R¹² iscycloalkyl or substituted pyridinyl, wherein substituted pyridinyl issubstituted with one to three substituent independently selected fromalkyl and halogen.
 6. The compound according to claim 1 wherein R¹² iscycloalkyl.
 7. The compound according to claim 1, R¹² is substitutedheteroaryl, wherein substituted heteroaryl is substituted with one tothree substituent independently selected from alkyl and halogen.
 8. Thecompound according to claim 1, wherein R¹² is substituted pyridinyl,wherein substituted pididinyl is substituted with one to threesubstituent independently selected from alkyl and halogen.
 9. Thecompound according to claim 1 wherein R¹ and R² are independentlyselected from H and alkyl.
 10. The compound according to claim 1 whereinR¹ and R² are alkyl.
 11. The compound according to claim 1 wherein R¹and R² are methyl.
 12. The compound according to claim 1 wherein m, nand p are zero.
 13. The compound according to claim 1 wherein w is 1 or2.
 14. The compound according to claim 1 wherein R³ and R⁴ are H. 15.The compound according to claim 1, wherein R⁵, R⁷ and R⁹ are H.
 16. Thecompound according to claim 1 wherein R⁹ is H and R¹⁰ and R¹¹ togetherform —(CH₂)_(w)—.
 17. The compound according to claim 1 wherein R¹⁴ isH.
 18. The compound according to claim 1 wherein R¹³ is chloro.
 19. Thecompound according to claim 1, wherein R¹⁵ is H.
 20. The compoundaccording to claim 1 selected from5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[[(3 S or3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[[(3 S or3R)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3H-isoindol-1-one;5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;6-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;6-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;6-Chloro-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;5-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl]amino]pyridin-3-yl]isoindol-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;6-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;6-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;5-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;(3R or 3S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;(3S or3R)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;(3R or 3S)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one;(3 S or3R)-5-Chloro-2-[5-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl-isoindolin-1-one;(3R or 3S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one;(3 S or3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one;2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;2-[5-[(1-Cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;2-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;2-[5-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;or a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1 selected from5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-2-[5-[[(3 S or3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindol-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;6-Chloro-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;(3R or 3S)-5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindolin-1-one;2-[5-[(1-Cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;or a pharmaceutically acceptable salt thereof.
 22. A process to preparea compound according to claim 1 comprising a) the reaction of a compoundof formula (II) in the presence of a compound of formula (III);

or b) the reaction of a compound of formula (IV) in the presence of acompound of formula (V);

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, A,m, n and p are as defined in claim 1 and X in step a) is halogen ortriflate and in step b) is halogen.
 23. A pharmaceutical compositioncomprising a compound according to claim 1 and a therapeutically inertcarrier.